Methods of and devices for chemical and threshold-gated electrical neuro-immuno-stimulation that triggers the stem cell growth to restore bodily functions

ABSTRACT

A method of reducing pain and induce/enhance the stem cell growth/differentiation reaction includes identifying a pair of related Noxipoints on an identified muscle/organ and applying a chemical/electrical stimulation to the pair of Noxipoints.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation-in-part application of the U.S.patent application Ser. No. 13/396,605, filed Feb. 15, 2012, which ispublished as U.S. Patent Application Publication No. 2012/0209348, andentitled “Nocipoint Therapy: Threshold-gated ElectricalNeuro-Immuno-Stimulation Procedure,” which claims priority from U.S.Provisional Patent Application Ser. No. 61/443,258, and titled“Threshold-gated Electrical Neuro-Immuno-Stimulation Procedure,” filedFeb. 16, 2011, which are all hereby incorporated herein by reference intheir entirety for all purposes.

Further, this application claims priority from U.S. Provisional PatentApplication Ser. No. 61/944,216, filed Feb. 25, 2014 and entitled“Pharmacologic and non-pharmacological Solutions that trigger the stemcell growth to restore bodily functions permanently,” which is herebyincorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

At least one embodiment of the present invention pertains to medicalprocedures and more particularly, but not exclusively, to reducing painand restoring bodily function through electrical stimulation ofNocipoints.

BACKGROUND OF THE INVENTION

Chronic skeletal-muscular pain costs the US $200+B a year and increasingin terms of loss of time and medical expenses according to the 2011 CDCreport. However, they are merely the manifestation of the underlyingcauses—skeletal-muscular injuries or pinched nerves.

Skeletal-muscular injuries from car accidents, sports, exercises, suddenmovement, wrong postures or sometime unknown reasons are the major causeof such pain. Standard self-care process includes cold/heat pads andgood rest for a period of time. In many cases, especially in acutecases, the body recovers; the muscle injury heals, and the paindisappears. Unfortunately, many people, 112 million in the US, get stuckwith chronic pain, according to the CDC report.

Pinched nerves at spinal cord cause pain syndromes or loss of motorcontrol at extremities (arms and legs). When a motor nerve is pinched,the patient experiences weak muscle response or even loss of motorcontrol of the affected arm/leg. When a sensory nerve is pinched, thepatient experiences tingling sensation, numbness in certain areas of theaffected arm or leg. Herniated discs are often cited as the cause of theproblem in radiological interpretation of CT scans. However, it ismisleading because (1) most herniated discs do not even touch the nearbynerve and thus not necessarily cause any pain, and (2) herniated discsoccur even in normal people with no pain or known injury. Most pinchednerve problems, as our clinical study indicates, are actually caused byinjuries of the muscle groups that support and balance the spine. Whenthe injuries of those corresponding muscles, mostly near the neck or thelower back, are healed, the pinched nerve problem and any associatedpain disappear as well.

Standard treatments for chronic pain typically include physical therapy,pain medication, epidural injection of steroids, and surgeries. Thetreatment process is long and ineffective: Majority of the patients hadlittle or no improvement after six months or longer of varioustherapies. The epidural injection is useful to reduce neuralinflammation. However, most of the chronics pains described above arenot neural inflammation. Thus, majority of patients either experience noimprovement or temporary improvement with a rebound in a few days or fewmonths when the epidural steroid wears off. In addition, due to theserious side-effect of steroids, epidural injection can only be used forseveral times. The prognosis of surgery was even less positive. Most ofpatients who undergo such invasive surgeries on and after six-monthrecovery periods found that their conditions are not better or evenworse than before the surgery. Pain medications, including bothprescription anti-inflammatory drugs and over-the-counter analgesicmedicine, are often used to relieve the pain temporarily and reduce theinflammation hoping that the body will heal the injury itself onceinflammation is reduced. For some patients with acute injury, the painmedication will bridge them through the recovery process with less or nopain. Unfortunately, chronic pain patients usually experience temporaryrelief with medications. The pain returns within hours after medicationis taken. In essence, majority of people who have chronic pain would gothrough multiple years of treatments without a permanent cure.

Based on extensive systematic review of medical and biological articles,when organ (such as muscle) tissues are injured (which can be inflictedby physical harm, disease, infection, degeneration, etc.), it cantrigger a cascade of the healing process mediated by innate immunesystem: The injured muscle/soft tissue triggers the release of cytokines(chemicals carry signals to promote or inhibit immune responses), whichrecruit the innate immune cells (e.g., macrophages) to take away thedead and injured tissue cells or the scar tissues around them.Macrophages in turn release other cytokines (e.g., IGF-1, TNF-alpha,hepatocyte growth factor (HGF) and protease) and trigger the cascade ofthe muscle tissue repair and regeneration. In normal cases, the immuneand regenerative process eventually heals the muscle. Unfortunately, theprocess often gets interrupted and never completes. Interruptiveprocesses include:

-   -   Scar tissue formation (b-FGF→fibroblast→fibrosis→scars)    -   Excessive and prolonged inflammation    -   Sheared muscle (structural damage of the connective        tissue/framework)    -   Age effect    -   Cycle aborted due to various environmental influences

When interrupted, the patient is stuck with the chronic pain and organinjury.

SUMMARY OF THE INVENTION

Our clinical study conducted in the application implicates thatnociceptors (i.e., pain receptors) of the muscle sensory nerve (esp.,the C-fiber) participate in the healing process and ensure the positivesignaling to the healing process and that the specific threshold-gatedelectrical stimulation procedure described in this application triggersthe neural signaling and thus the healing process on the immune systemside, based on the thousands of cases in which muscle injuries/painsrecovered within a few hours to a few days after the procedure.

In one aspect, the method comprises identifying a pair of Noxipoints,wherein the pair of In some embodiments, Noxipoints are located at twoends of a strain of organ (e.g., muscle) tissue/fiber and applying apredetermined electrical or chemical stimulation to the pair ofNoxipoints (in the case of skeletal muscles, Noxipoints are mainly atthe tendon near the attachments). In some other embodiments, theapplication a predetermined electrical or chemical stimulation to thepair of Noxipoints triggers a reaction of a neuroimmune cascade. Inanother embodiments, the chemical stimulation comprises nociceptivechemicals. In other embodiments, the nociceptive chemicals comprisecapsaicin. In yet other embodiments, the chemical stimulation comprisessubstance P, TNF-α, growth factors such as Insulin-like GrowthFactor-Type I (IGF-1) and Hepatocyte Growth Factor (HGF), or acombination of Substance P, TNF-α and/or growth factors.

In other embodiments, the electrical stimulation comprises increasing anapplying voltage until an occurrence of a soreness, an achiness, a dullpain, or a combination thereof. In some other embodiments, the methodfurther comprises adjusting an intensity, a wave length, a trainfrequency, a wave pattern of the applied electrical stimulation untilthe occurrence of the soreness, the achiness, the dull pain, or thecombination thereof. In some embodiments, the pair of Noxipoints islocated at two attachment ends of a muscle group.

In other embodiments, the pair of Noxipoints are located at two oppositesides of an organ. Some muscles are short and spread throughout theorgan (e.g., heart, stomach, kidney, liver, etc.), in which theNoxipoints are located throughout the organ. In some other embodiments,the applying a predetermined electrical or chemical stimulation to thepair of Noxipoints enhances a growth rate of one or more stem cells. Insome embodiments, the applying a predetermined electrical or chemicalstimulation to the pair of Noxipoints activates one or more satellitecells or other stem cells. In other embodiments, the applying apredetermined electrical or chemical stimulation to the pair ofNoxipoints increases a rate of self-healing process.

In another aspect, a treatment device comprises a user-interface controlpanel configured to receive an input of a response of an appliedelectrical stimulation and an electrical control circuit configured totune the applied electrical stimulation. In some embodiments, theresponse comprises feeling of a soreness, an achiness, a dull pain, or acombination thereof. In other embodiments, the electrical controlcircuit is configured to increase an applied voltage when an input isnot a feeling of a soreness, an achiness, a dull pain, or a combinationthereof. In some other embodiments, the device further comprises asoftware indicating a location of a corresponding Noxipoint of a pair ofNoxipoints. In some other embodiments, the software comprising a 3Dmodeling of a human anatomy.

In another aspect, a method of enhancing a healing process comprisesapplying a predetermined stimulation on a pair of Noxipoints andenhancing a rate of healing by applying the predetermined stimulation.In some embodiments, the predetermined stimulation comprises an appliedelectrical stimulation until an occurrence of a soreness, an achiness, adull pain, or a combination thereof. In other embodiments, thepredetermined stimulation triggers a signaling pathway of adifferentiation of one or more adult stem cells. In some otherembodiments, the predetermined stimulation triggers the generation orrelease of an amount of substance P.

In some embodiments, the predetermined stimulation makes a mast cell torelease a histamine and a cytokine. In other embodiments, the cytokinecomprises a tumor necrosis factor-alpha (TNF-α). In other embodiments,the predetermined stimulation causes a macrophage to conductphagocytosis on a scar tissue or an impaired tissue. In someembodiments, the predetermined stimulation comprises an externalapplication of an amount of substance P, TNF-α, growth factors or acombination of substance P, TNF-α and growth factors. In someembodiments, the term “Nocipoint” is interchangeable with the term“Noxipoint”.

BRIEF DESCRIPTION OF THE DRAWINGS

One or more embodiments of the present invention are illustrated by wayof example and not limitation in the figures of the accompanyingdrawings, in which like references indicate similar elements.

FIG. 1 illustrates a 59 year old patient injured his back after tryingto pick up a heavy box. Couldn't bend more than 20 degrees. Had lowerback pain.

FIG. 2 illustrates locating muscle group(s) responsible for the pain ofthe example patient.

FIG. 3 illustrates an example of locating a “Nocipoint.”

FIG. 4 illustrates tracing anatomically to find the second Nocipoint.

FIG. 5 illustrates an example case repeating the procedure on otherpairs of Nocipoints.

FIG. 6 illustrates within 25 minutes, the patient recovered after thefirst treatment with full motion range. No more back pain since then.

FIG. 7 is a chart illustrating relative pain levels BEFORE and AFTER theNocipoint Therapy.

FIG. 8 illustrates a patient before treatment.

FIG. 9 illustrates the patient after treatment.

FIG. 10 is a flow chart illustrating a restoring bodily function methodin accordance with some embodiments of the present invention.

FIG. 11A illustrates a method that restores impaired bodily functionsvia the division and proliferation of progenitor stem cells inaccordance with some embodiments of the present invention.

FIG. 11B illustrates an electrical potential applied noxipoint therapyprocess in accordance with some embodiments of the present invention.

FIG. 11C illustrates a noxipoint therapy on an upper part of theimpaired trapezius in accordance with some embodiments of the presentinvention.

FIGS. 12A-12E illustrate a noxipoint stimulating device and method ofusing the device in accordance with some embodiments of the presentinvention.

FIG. 12F illustrates the result of NK-like treatment to chronichypersensitivity in a rat study in accordance with some embodiments ofthe present invention.

FIG. 13 illustrates a reversed paw sensitization and a restored functionusing a treatment in accordance with some embodiments of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Nocipoint StimulationTherapy—A Threshold-Gated Electrical Neuro-Immuno-Stimulation:

The Nocipoint Stimulation Therapy is a process using electricalstimulation in a precise manner that activates the complete healing of(1) muscle injury with associated local pain, and (2) muscle injury thatcauses pinched nerve and indirectly causes remote pains and/or loss ofmotor control at the extremities (legs, arms) in a short time:

Steps:

-   -   (1) The patient identifies the general area of the pain: (e.g.,        the left shoulder/the lower left back)    -   (2) Decide whether the pain is caused by the muscle(s) locally        or a pinched nerve at the spinal cord remotely. In the latter        case, find the muscle groups that structurally support the        vertebrae near the pinched nerve. A few tests are well        documented in clinical diagnosis to differentiate local muscle        pain from pain/muscle weakness caused by pinched nerve. To name        a few:        -   a. Injury history: If someone springs his/her ankle, the            ankle pain is most likely caused by local injury.        -   b. The local pains are usually associated with certain            movement and will always present when the same movement is            performed.        -   c. The pain caused by pinched nerve often can be temporarily            relieved by changing the patient's posture s or via spinal            traction. These maneuvers can be used to differentiate the            pinched nerve problems from local muscle injuries. However,            the pain will come back soon afterward.    -   See FIG. 1. Example: A 59 year old patient injured his back        after trying to pick up a heavy box. Couldn't bend more than 20        degrees. Had lower back pain.    -   (3) Use the human anatomy to locate the muscle(s) that is likely        to be responsible for the identified pain area above. This        research has found that the anatomical layout of each muscle and        its expected kinetics is critical in identifying the muscle. A        3-D anatomy model will be useful for this.        -   See FIG. 2. Locate muscle group(s) responsible for the pain    -   (4) Find the first “Nocipoint”: Based on the candidate muscle        group(s) identified above, press at or near one of the insertion        points of the muscle(s), and find the “Nocipoint”. This research        has discovered that a “Nocipoint” is a small area located at the        end of an injured muscle tissue and is painful only when        pressed/touched. These Nocipoints are very sensitive to even        light presses, but patients usually did not feel any pain there        if not so touched. The patient will experience sharp/noticeable        pain when the Nocipoint is touched. Anatomically, they are where        the nociceptors of the muscular sensory nerve (i.e., the free        nerve endings) are.        -   See FIG. 3. Example: Locate a “Nocipoint”    -   (5) Find the second matching “Nocipoint” by tracing the muscle        in anatomy map: For each muscular injury/pain, one will ALWAYS        find another “Nocipoint” near another insertion point at the        other end of the muscle. Certain muscle groups with more than        two insertion points will have multiple corresponding Nocipoints        at the group level. Patients are often surprised by the presence        of these pressure-induced pain points. Sometimes one of the        Nocipoints is far away from the perceived painful area. Thus,        following the muscle anatomically is critical to precisely        locate the matching Nocipoints. Note that, while there may be        more than two insertion points/ends of a muscle group (e.g.,        triceps), there are always exactly two ends of at the muscle        fiber level, and thus two Noxipoints per muscle fiber. In other        muscle groups (e.g., smooth muscle, cardiac muscle), Noxipoints        are evenly distributed among the injured area of the organ, as        the muscle cell in these types of muscle groups are typically        short, and thus the two ends of the Nocipoints are very close to        each other. In the case of brain, Nocipoints are outside of the        skull around the head due to referral pain extended from the        damaged neurons.        -   See FIG. 4. Trace anatomically to find the second Nocipoint    -   The Nocipoints described here always come in pairs. No prior art        has ever figured out that it requires a PAIR of the matching        painful points per muscle group to induce the injury curing        process.    -   The complexity comes in when multiple groups of muscles in the        same area are injured. In such cases, multiple Nocipoints        (sometimes as many as 4-6 points) may express in the nearby area        and should be paired respectively based on the muscle anatomy.    -   (6) Noxipoint Stimulation Therapy: In order to trigger the        responses of the C-fiber nerve nociceptors, the electrical        stimulation at the neuron needs to fall within a narrow range in        order to activating the neuro-immune cascade and gain the        optimal curing effect. The signaling process of the sensory        nerve has the following thresholds subcutaneously:        -   a. The firing threshold (when the depolarization of the            neuron cell starts): around +/−10 mV at the neuron        -   b. The action potential (when the depolarization ends and            repolarization of the neuron cell starts): around +/−60 mV            at the neuron.    -   Based on the biofeedback of the patients in this study, it is        evident that the electrical stimulation needs to be between the        two thresholds to have curing effect. However, due to the high        resistance (100K to 1.3 M Ohm), the stimulating pulse at the        skin surface degrades quickly before it reaches the free nerve        ending (neurons) of the nocireceptor. It needs to be at much        higher voltage/amplitude than what is measured at the neuron.        Some clinical examples of the operating stimulations at skin        surface (i.e., transcutaneous electrical nerve stimulation,        TENS) are as follows:

Pulse Operating range of Wave pattern frequency pulse amplitude Squarewave/Sine wave  9 Hz 130 V-170 V Square wave 20 Hz 70 V-95 V

-   -   Note that the two transcutaneous stimulation patterns above        match with the known behaviors of the spatial and temporal        summation of the action potential at the sensory nerves, and        typically needs a train of impulses. While the first pulse        pattern has higher amplitude range, recruiting enough nerve        endings to propagate the pain-signal; the second pattern works        just as effective with a faster pulse (20 Hz vs. 8 Hz) yet lower        amplitudes. There are numerous combinations of (frequency,        intensity) pair to induce successful effect; but one of the        important factors includes C-fiber-like sensation (soreness,        achiness, sense of fatigue, dull pain, etc.)    -   Given that every person varies in age and sensitivity to pain,        minor adjustments are needed sometimes: Further adjust the        strength/frequency/wave pattern above the “firing potential” and        within the “depolarization” range of the nociceptor. In certain        embodiments, the working frequency range can be as high as about        70 Hz.    -   A simple biofeedback can be used to “calibrate” the stimulation        setting: when the patient starts to feel a sensation of deep        pressure-induced-dull-pain (i.e., when C fibers of the sensory        nerve are triggered), but not a muscle spasm or sharper pain,        the nociceptor is by definition above the firing potential and        below the action potential thresholds. It is known that the        C-fiber transmits “dull pain” or “soreness” signals (instead of        the sharp pain). Thus, the patient-provided biofeedback of        feeling the dull pain confirms that the electrical stimulation        is within the above thresholds. That is the operating range of        the Nocipoint stimulation. It is often more than once (up to        three or 3.5 times) the intensity of activating the motor nerve        in the area.    -   Note that all values above and below are approximate.    -   (7) For each pair of Nocipoints, carefully control the        stimulation duration within a tight range between 1 minutes to        15 minutes. Minor variance is alright based on age and muscle        tone, but excessive long time does not necessarily yield the        best healing result.    -   (8) Repeat the process on other muscle if necessary: If the        correct pair of Nocipoints is stimulated, the patient will        experience instant relief of pain of the stimulated muscle. And        within a few minutes, the muscular function starts to heal and        recover. Typically, however, multiple muscle injuries        collectively cause the pain. Thus, repeat the same process to        all other pairs of the Nocipoints.    -   See FIG. 5. Example case: Repeat the procedure on other pairs of        Nocipoints    -   (9) When all pairs of Nocipoints for the injured muscle groups        are identified anatomically and stimulated, the process is        complete. Pains will be relieved and patient will be able to        regain functions after several days (during which the cells are        remodeled). Typically, it will be completed within 2-8 hours in        1-5 sessions.        -   See FIG. 6. Within a couple of hours, the healing process            starts, and eventually functional recovery occurs.    -   (10) Resting period: Immediately after the treatment is        complete, the patient should go easy on the just-recovered        muscles. These muscles take several days to heal and the        tissues/fibers may not be strong enough after initial healing.        To prevent new injury to the same muscle, wait for several days.        For people who are aged or weak muscles, avoid extraneous uses        for at least about one week. For young people or people with        strong muscle tone, about 3-4 days of resting (of the treated        tissue) are advised. During the resting period, some light        exercise can be performed to train the newly healed muscles.

Control Study

-   -   1. Patient profiles:        (a) Pain/tingling sensation at extremities or loss of motor        control due to pinched nerves, which may or may not be present        all the time. Most of them had functional deficiencies. Ages:        35-65        (b) Chronic neck pain and back pain for various (sometimes        unknown) reasons, having lasted 2-20 years. All had tried many        treatment protocols (physical therapy, epidural injection,        acupuncture, massage, etc.) without notable improvement. Many        were also on prescribed analgesics. Patients' ages are between        30 and 79.        (c) Lingering pain at extremities due to sports injuries, car        accidents, or sudden movements. Many were functionally impaired        for over 3 months (some multiple years). The age group: 15-68        (a) and (b) groups often had multiple areas of pain while        Group (c) often had localized pain. Most of them experienced        functional constraints of their arms, legs or the back. Many had        symptoms from both tissue injury and pinched nerve. They were        classified in either (a) or (b) for convenience. Many felt        depressed, some showed allodynia or hyperalgersia. In general,        these patients were all stuck with chronic pains and impaired        muscular functions for a long time.

The Treatment Procedure:

The patients were given the Nocipoint Therapy: Electrically stimulatecertain stimulation points that were anatomically relevant to injuredtissues/sites with controlled timing, strength, dosing, etc. Becausemost patients had multiple problem areas, each session typically lastedfor 1.5 hours.

The results (based on a study of 64 chronic pain patients):

100% patients recovered with full range of motion and only less than 10%reports Level 1 or 2 out of 10 remaining pain. 89% of patients recoveredin 1-4 sessions. Full recovery is defined as (1) gaining full range ofmotion (age appropriate) and (2) persisting function for at least onemonth without recurring pains.

Recovered in # of Remaining pain (x/10) level sessions # of patientspercentage when treatment stopped 1 7 10.9% 0-1 2 16 25.0% 0-notnoticable 3 19 29.7% 0-not noticable 4 15 23.4% not noticable-1  5+ 710.9% 1-2 ** 64 total

Most patients experienced substantial or complete recovery of musclefunction in the first one or two treatments. Later sessions weretypically dealing with secondary/other pains that were not in thepatients' chief complaint initially. (That is, when the primary problemis cured, the patient's perception starts to notice secondary and otherpains.)

Arm and hand pains typically involve more muscle groups and often takelonger time than neck/lower back pains.

People who had extensive tissue damages required multiple sessions/moretime to cover all the damaged tissues/muscle groups. Some patients whowent through 4 or 5+ sessions stopped coming because they were happywith the substantial improvements.

Control-Test Analysis

Chronic pain patients typically have persistent pain for months oryears, with other conventional treatment/therapy (See FIG. 1). Thepatients who received the Nocipoint Therapy experienced substantial painrelief and regained function immediately after the treatment. Unlike allprior arts, the recovery persisted. The control in this study is thehistorical pain level before the treatment, while the test is the painlevel afterward the treatment (in the AFTER scenario).

-   -   See FIG. 7. Relative pain levels BEFORE and AFTER the Nocipoint        Therapy    -   In order to have a meaningful aggregation across all patients,        the pain levels are normalized at the time right before the        treatment. That is, they are defined as relative pain compared        to the pain level right before the Nocipoint Therapy. Chronic        pain patients typically have persistent pain for months or        years, with or without conventional treatment/therapy, as        indicated in the BEFORE scenario. Patients who received the        Nocipoint Therapy experienced substantial pain relief and        regained function soon after the treatment (the AFTER scenario).        Notice that the recovery persisted afterward. (Note: history        earlier than 84 days before the treatment were ignored in this        chart.)

Observations:

All treatments were done within one to several hours accumulatively,spreading over one or a few sessions. The gap between sessions has minorimpact on recovery, positive or negative. That is, patients technicallycan complete all sessions consecutively in a short period.

Patients usually experienced immediate improvement/cure when the correctNocipoints are stimulated. This contrasts the 1-2 years of standard painmanagement protocol. The Nocipoint Therapy is precise, reproducible, andwith near-perfect success rate.

Elimination of the placebo effect: During a session, if the points forstimulation were off by a little from the intended points mistakenly(e.g., by ½ inch), or by a lot intentionally, the patient could tell andwould instantly indicate the lack of improvement. Correcting thestimulation location to the right Nocipoints will enable instant result.

After each session, the patients were instructed to go easy on exerciseswith the newly recovered muscles for a few days or a week for seniors,to prevent new injuries before the tissue gains enough strength.

In sum, the procedure cures pains permanently and persistently. Moreimportantly, it heals injured tissues and restores functions. It isrepeatable and the same results occur in nearly all cases.

A recent example: (with patient's permission):

The patient is 59, who injured his lower back a week before thetreatment while picking up a heavy box. Had been in pain and had to rolloff the bed every day. Worn waist support all days to avoid pain.

Before the treatment: See FIG. 8: the maximum angle he could bendwithout waist support)

After a 25-minute treatment: Full range of motion recovered. No painsince. See FIG. 9.

Note that any and all of the embodiments described above can be combinedwith each other, except to the extent that it may be stated otherwiseabove or to the extent that any such embodiments might be mutuallyexclusive in function and/or structure.

Although the present invention has been described with reference tospecific exemplary embodiments, it will be recognized that the inventionis not limited to the embodiments described, but can be practiced withmodification and alteration within the spirit and scope of the appendedclaims. Accordingly, the specification and drawings are to be regardedin an illustrative sense rather than a restrictive sense.

Pharmacologic and Non-Pharmacological Solutions that Trigger the StemCell Growth to Restore Bodily Functions Permanently

In the following, methods of and devices for permanently restoringbodily functions using pharmacologic and non-pharmacologic solutions aredisclosed. In some embodiments, the present invention is used totreat/cure the underlying causes, symptoms (often manifested as pains).

FIG. 10 is a flow chart illustrating a restoring bodily function method1000 in accordance with some embodiments of the present invention.

The method 1000 can start at Step 1002. At Step 1004, a first Noxipointis identified. In some embodiments, the Step 1004 is performed byidentifying a general pain area, which is able to be done by a patient,a sensing device, or a medical professional, palpating the organ (e.g.,in the case of muscle, at attachment points (origin and insertion) ofeach muscle group and soft tissue) within or near the pain area, andidentifying a set of pain points sensitive to pressure (e.g.,Noxipoint).

At Step 1006, a second Noxipoint that is a specific locationcorresponding/associating with the first Noxipoint is identified. Insome embodiments, the Step 1006 is performed by locating a correspondingtissue cluster (e.g., a muscle group or soft tissue) as a target ofstimulation applying point. The first and the second Noxipointsgenerally appear on both of the tissue cluster attachments (e.g., at thetwo terminal points of a strand of a muscle fiber). Noxipoints aregenerally existing in pairs. For example, a second correspondingNoxipoint can be located when a first Noxipoint is located. Further, asecond set of plural Noxipoints can be found when a first set of pluralNoxipoints are found. The first set and the second set of the Noxipointsare generally located at two terminal ends/points of a group of musclefibers.

At Step 1008, a predetermined stimulation is applied at the first, thesecond, or both of the Noxipoints. In some embodiments, thepredetermined stimulation comprises a physical stimulation, a chemicalstimulation, or a combination thereof, such as a chemical inducedphysical stimulation or a physically induced chemical/physiologicalresponse. For example, the physical stimulation comprises an appliedelectrical power/voltage stimulation and the chemical stimulationcomprises an applied chemical stimulation, such as injection of apredetermined amount of chemical substances.

In some embodiments, chemical stimulations (such as nociceptivechemicals; e.g., capsaicin) are applied at the precise spot of theNoxipoints of the target muscle/tissue cluster identified in Steps 1004and 1006 via injection or by using a cutaneous patch. In someembodiments, substance P, TNF-α, or a combination of TNF-α and growthfactors (such as IGF-1) are applied at the precise spots of theNoxipoints. Nociceptive chemicals, substance P, TNF-α, and/or acombination of TNF-α and growth factors are able to be applied at thesame time at the target muscle/soft tissue. The applications are able tobe used at multiple sites simultaneously.

In some embodiments, straining treated areas are avoided during a“resting period” after each treatment and braces are used in moderate orsevere cases. Patient is advised not use or strain the newly treatedmuscle/tissue during the “resting period” for 1-10 days or a minimum ofthree days. If the patient has extensively impaired muscles, they areadvised to take two more days of resting. The method 1000 can stop atStep 1010.

FIG. 11A illustrates a method 1100 that restores impaired body functionsvia the division and proliferation of progenitor stem cells inaccordance with some embodiments of the present invention.

The method 1100 illustrates an induced cellular signaling pathway thatactivates the mechanisms for repairing and regenerating organ/tissuecells. The stimulation on the Noxipoints causes the C-fiber nociceptor1102 to emit substance P 1104, which in turn triggers the mast cell (MC)1106 or other immune cells on site to release histamine and TNF-α 1108.TNF-α 1108 recruits the macrophage 1110 locally to conduct phagocytosison scar tissues/impaired cells 1112 and to release growth factors 1114(such as IGF-1) that activate the differentiation of progenitor stemcells 1116 (such as myo-satellite cells) in the neighborhood, which inturn repair the impaired muscle/tissue. Other growth factors produced bythe macrophage that are myogenic for satellite cells includetransforming growth factor-beta (TGF-β1118 and basic fibroblast growthfactor (FGF) 1120, which promote chemotaxis of satellite cells 1116 inthe tissue toward the impaired site. Macrophages release additionalTNF-α 1108 locally that recruits more macrophages, further expeditingthe process. In addition, Sub P 1104 or other downstream cytokine/growthfactor in this signaling pathway promotes angiogenesis besidesmyogenesis mediated by satellite cell proliferation and division. Insome embodiments, an amount of substance P, TNF-α, or a combination ofTNF-α and growth factors are able to be applied on the Noxipoint totrigger/enhance the signaling pathway as described above.

FIG. 11B illustrates an electrical potential applied Noxipoint therapyprocess in accordance with some embodiments of the present invention. ANoxipoint stimulation device 1130 comprises a positive terminal 1130Aand a negative terminal 1130B. The positive terminal 1130A couples witha first applying point 1132 and the negative terminal 1130B couples witha second applying point 1134. The first and the second applying pointsare located at the two terminal ends of a muscle fiber 1138. Thepositive terminal 1130A, the first applying point 1132, the secondapplying point 1134, and the negative terminal 1130B form a closedelectrical circuit loop 1136. In some embodiments, the first applyingpoint and the second applying point form a pair of Noxipoints, whichcouple with c-fibers 1138.

FIG. 11C illustrates a Noxipoint therapy on an upper part of theimpaired trapezius in accordance with some embodiments of the presentinvention. A first Noxipoint 1140A has a corresponding second Noxipoint1140B, where the first and the second Noxipoints are located at twoterminal ends of a muscle fiber. Similarly, a first noxipoint 1142A hasa corresponding second noxipoint 1142B.

FIGS. 12A-12D illustrate a Noxipoint stimulating device 1200 inaccordance with some embodiments of the present invention. The devicecomprises a display with buttons 1202 (e.g., on a GUI-Graphical UserInterface), each of which represent a sensation, and a mechanism todepress the buttons (e.g., mouse, touch screen, or voice command), anelectrical stimulator 1204 with a range of controllable parametersincluding voltage, wave pattern, train frequency, timer, and acommunicating/control mechanism 1206 with a programming interface. Thedevice 1200 comprises a pair of electrical pads 1208, such that thedevice 1200 is able to generate electrical pulses on a user.

In some embodiments, the display with buttons 1202 comprises varioususer interfaces, such as a dial type 1202A (FIG. 12B), which allows auser to increase/decrease an applying voltage by turning the dial. Insome embodiments, a graphical user interface (GUI) 1202B provides aselection menu allowing a selection of patient's feelings. By selectinga pre-set feeling, the device 1200 is able to adjust its applied pulse,duration, strength, among other factors. A person of ordinary skill inthe art appreciates that the user interfaces are able to be adjusted andprogrammable. For example, each possible sensory response to theelectrical stimulation is indicated as a button on the control panel.Each such button corresponds to a different predeterminedincrement/decrement of the parameters of the electrical stimulation inthe Noxipoint device. When the user presses a button, the correspondingchange is performed continuously. When nothing is pressed, it maintainsthe same setting. The zone 1202C indicates the terminal state. When anyof the buttons 1202D is pressed, the setting of the Noxipointstimulation device is fixated or the change substantially slowed downuntil further instructed.

In some embodiments, the device 1200 comprises a 3D modeling software(Noxipoint Navigation system) as shown in the FIGS. 12C and 12D, whichshow the locations of the corresponding Noxipoints based on the humananatomy. For example, when a first Noxipoint 1212A is selected due tothe patent's expression of pain and soreness, the correspondingNoxipoint 1212B is identified by the software system of the presentinvention, such that an application of a stimulation on the secondNoxipoint can be performed.

In the following, a Noxipoint process (NP) performed using the device1200 is illustrated in accordance with some embodiments of the presentinvention. The device 1200 is able to perform unique stimuli with one ormore of the following characteristics: anatomic-site-specificstimulation (at corresponding Noxipoints of each target tissue),intensity-and-submodality-specific setting (eliciting soreness or dullpain but not sharp pain) and brief duration of the stimulation.

The process is able to be performed as follows:

(1) based on the general pain area identified by the patient, palpatethe organ (e.g., at attachment points (origin and insertion) of eachmuscle group and soft tissue in the case of skeletomuscular cell; orwhere the nociceptors of the organ are) within or near the pain area,and identify a set of pain points sensitive to pressure (e.g.,Noxipoint). A cluster of myocells or soft tissue cells is identified asa target when Noxipoints appear on both of its two ends;(2) the stimulation pads/needles are precisely placed at the locationsof the pair of Noxipoints corresponding to the impaired targetmuscle/tissue (the target) identified in (1) for about 4-5 minutes perapplication. For internal organs, stimulation pads/needles are placed atmost painful pairs of the identified Noxipoints. After each application,a new pair of target Noxipoints is identified for the next pad/needleplacement and application. Multiple pairs of Noxipoints are able to bestimulated at the same time;(3) the stimulation is set to induce the specific nociceptivesubmodality of moderate soreness, achiness or mild dull pain (which isthe signature sensation of the C-fiber nociceptor) based on thepatient's confirmation during the application. Intensity, wave length,frequency and wave pattern/mode are adjusted collectively to achievesuch sensation.

In some embodiments, the setting to achieve such sensation for eachmuscle group (e.g., deltoid) is not a constant but varies greatly fromperson to person (e.g., 92V, 300 μsec train-length, 2 Hz or Burst modevs. 55V, 50μsec train-length, 3 Hz, Burst mode).

As shown in FIG. 12E, the settings to reach the target state(sorness/achiness/mild dull pain) in an example application to aparticular muscle (e.g., gastrocnemius) among several subjects varywidely. The setting/controlling parameters include applied wave type,the frequency, and the pulse. In some embodiments, the therapist/userused the device 1200 to reach the soreness/dull pain state smoothly inthe stimulation process.

In some embodiments, the device 1200 comprises a touch screencomputer/smart phone device interfaced/integrated with an electricalstimulator. In some embodiments, the process disclosed herein can beenhanced by combining the steps in the above mentioned drug and deviceprocesses. By providing drug at or near the target site to be treatedand stimulating the impaired tissue (organ), the integrated processdelivers the drug precisely at the site where the drug is needed withstronger doses than what the body naturally can produce.

Clinic Testing and Experimental Results

The methods and devices disclosed herein are able to induce stem cellgrowth or functional restoration/healing. These evidences existed inmultiple biofields.

a. Successful Cases (Table 1)

TABLE 1 Specific Symptoms/Condition before Outcome after Organ CasesNoxipoint Therapy Noxipoint Plantar Chronic and debilitating sharp heelFully functional in fasciitis pain exacerbated by bearing weight waling,running. (8 patients) on the heel after prolonged periods of Free ofpain at any rest. Individuals with plantar time. fasciitis reported mostintense pain No pain reported occurred during their first steps afterweeks after the getting out of bed or after sitting for treatment(treatment a prolonged period and subsequently session). improves withcontinued walking. Numbness, tingling, swelling, or radiating pains arerarely reported symptoms. Heart Case 1 & 2: Symptoms: Frequent shortnessof No more symptoms valvular breath, chest pressure. after 2 sessions ofregurgitation Case 3: Mitral value regurgitation. treatments (3patients) Symptoms: Frequent shortness of Breath normally. breath, chestpressure. Evidences: After 2 sessions of Abnormal ECG and ultrasoundtreatments, results. Symptoms: None Evidences: Both ECG and ultrasoundindicated normal. Rheumatoid Symptoms: No more pain Arthritis (6 Pain(often symmetric) at fingers immediately and 3 patients) and/or toes.months after 2-4 Disfigured fingers/toes. treatments Acid RefluxSymptoms: No more symptoms (5 patients) Heartburn, after 1-2 sessions ofRegurgitation treatments Interstitial Symptoms: Chronic severe andNormal urination Cystitis/bladder pain constant suprapubic pain, urinaryand sexual syndrome frequency, painful sexual intercourse intercourseafter (IC/BPS) and nocturia. treatment. (1 case) Evidence:fiberized/damaged No more nocturia or urothelium (or bladder lining)pain after 2 treatments. Evidence: bladder normal. No more visiblefiberization Scoliosis Symptoms: curved spinal cord, 4/6 patients had (6patients) ranging from 25 degree to 53 degree. visibly straighter spineand all pain was removed after 2-7 treatments. Evidence: curved spine inX ray Evidence: Two image patients who had follow-up X rays indicatingstraighter spine. Frozen Refer to the Movement of the shoulder (Range ofRanges of motion shoulder/Adhesive IRB motion) is severely restricted,with became normal or capsulitis of approved progressive loss of bothactive and nearly normal after shoulder clinical trial passive range ofmotion. The 2-4 treatments. (100+ report at condition is sometimescaused by Pain-free patients) Pain Cure injury, leading to lack of usedue to movements. Center pain, but also often arises spontaneously withno obvious preceding trigger factor. Painful in arm movements. ChronicRefer to the Movement of the neck is moderately Ranges of motioncervical pain IRB-approved or severely restricted, with became normal or(200+ clinical trial progressive loss of both active and nearly normalafter patients) report at passive range of motion. The 2-4 treatments.Pain Cure condition is sometimes caused by Pain-free Center injury,leading to lack of use due to movements. pain, but also often arisesspontaneously with no obvious preceding trigger factor. Migraine 12cases Periodic severe headache. No more headache (15 patients) 3 casesSevere constant headache. Symptom remained after 1-2 treatments.Menstrual pain Periodic pain during menstrual MP never recurred (5patients) periods after 1-2 sessions in 4/5 cases. One patient who didnot recover did not return after one treatment. CerebrovascularUnilateral paralysis of extremities. Passive pain and accident Stiffnessof the affected area and stiffness were (CVA)/Strokes pain duringpassive movement. relieved in all (5 patients) patients. Two patientsregained movement/range of motion recovered after 4-6 sessions.b. In Vitro Testing

In vitro testing shows that the substance P triggers the innate immuneresponse, likely starting with the mast cell (MC) on site to releasehistamine and one type of cytokine, tumor necrosis factor-alpha (TNF-α).MC only releases TNF-α upon receiving the substance P signal, eventhough MC is also capable of producing other cytokines (e.g., Interlukin-1 (IL-1), IL-3, IL-4, IL-6). TNF-α recruits the macrophage to conductphagocytosis on scar tissues or impaired cells and to release growthfactors (such as insulin-like growth factor type 1, or IGF-1) thatactivate the differentiation of adult stem cells (e.g., satellite cellsin the muscle) which in turn repair the impaired muscle/tissue. Othergrowth factors produced by the macrophage that are myogenic forsatellite cells include transforming growth factor-beta (TGF-β) andbasic fibroblast growth factor (FGF), which promote chemotaxis ofsatellite cells in the tissue toward the impaired site and inhibit themafter activation.

An animal model test on rats in the lab proved that the presenttreatment process worked.

The Protocol:

The standard chronic pain model of acid injection is used as thebaseline in the animal model test of the present treatment. Acid isinjected into the left leg of six rats (unilateral injection) and inducechronic pain in both sides of hind paw. 6 rats are randomly divided into3 groups (2 rats per group); 3 different stimulus intensities areapplied on the left leg of 6 rats for 3 minutes: 1T, 2T and 3T Noxipointstimulations. T is the stimulus threshold of muscle twitching. Note thatthis is translated from the earlier finding of human subject in terms ofthe relative intensity of Noxipoint stimulation between observedtwitching (muscle contraction) and reported medium soreness.

Paw withdraw threshold of plantar hindpaw in the ipsilateral (A) andcontralateral side (B) to the acid injection is used as the measurementof pain/functional deficit.

Before acid injection, rats could sustain with 15 g von frey stimulationapplied on the plantar surface of hind paw. After acid injection,ipsilateral and contralateral side of hind paw skin became sensitized(withdraw threshold is down to 4-8 g).

Note that the acid injection (injecting acid twice at the leg muscle)has been used as the standard way to induce chronic pain. Once induced,the pain will stay for a long time. Most analgesic drugs couldtemporarily reduce the pain but could not maintain the result.

Results:

As shown in FIG. 13, the present treatment is shown to have reversed thepaw sensitization (withdraw threshold went back to 10-15 g) and restoredthe function persistently/permanently. Functional tests of treadmilltest show similar results.

C. Clinical Evidences

It is shown that Noxipoint Process (NP) signaling pathway repairs andrestores the muscle. A prospective, blinded randomized controlledclinical trial with crossover is conducted that compared the effect ofNP versus conventional Physical Therapy including TENS (PT-TENS) on painreduction, functional restoration and quality of life. To ensure thatthe functions are actually restored, the ranges of motion are measuredby assessors after the each and last session of application of NoxipointProcess, 4-6 week after the last session. The pain level was alsomeasured at the same time, and randomly followed up at 3-6 months afterthe treatment by phone.

At the follow-up (average 6 weeks after the last session), NoxipointProcess is found to restore all patients' functions to from an averageimpairment severity index of 10.3 (severe) to 2.3 (mild) (p<0.001)within three sessions of treatment. It is found to reduce the painsubstantially (BPI from 7.7 to 0.8, p<0.0001) while patients in thePT-TENS arm showed no significant change (from 8.1 to 8.2, p=0.84). 75%of the Noxipoint Therapy patients are fully functional and free in allranges of motion after 3 sessions of treatment. Quality of life measuresshowed significant comparative advantages of NT over PT-TENS (p<0.0001).The associated pain disappeared permanently as well.

Based on the clinical observations that (1) the pain was removed withinminutes after each treatment, and (1) the full functions of the patient,measured by ranges of motion, were recovered a few days after NPtreatment, the Noxipoint signaling pathway that caused cell remodeling(repair and/or regeneration) via adult stem cells was thus supported.

Multiple case studies on conditions otherwise intractable or untreatableby current medicine have shown the effectiveness of the novel Noxipointprocess. Evidences showed that Noxipoint Process could restore functionsof multiple organs besides the skeletomuscular ones, such as mitralvalve prolapse (with ECG and ultrasound images before and after),kidney, bladder and stomach. When the underlying condition is resolved,the associated pain disappeared as well.

Such substantial outcomes in functional restoration are unprecedented.None of the existing treatments or remedies have generated results withsuch high curing rate and restoration rate.

CONCLUSION

Applying the Noxipoint device and/or drugs on the Noxipoint SignalingPathway precisely at the Noxipoints of the impaired muscle triggers theadult stem cell growth and thus restores bodily functions on a permanentbasis. As a derived benefit, it naturally eliminates the associatedpain.

The drugs/chemicals including capcasin substance P, TNF-alpha, and/orgrowth factors such as IGF-1, applied on the dual Noxipoints thatactivate Noxipoint Signaling Pathway are novel and useful methods.

The electrical stimulation on the Noxipoint signaling pathway are novelfor stem cell regeneration/functional recovery. The precise location (atNoxipoints) and unique sensory of the stimulation (soreness/dull pain)in Noxipoint Therapy make the difference.

In some embodiments, the terms Nocipoint and Noxipoint, and the prefixesnoci- and noxi- are used interchangeably. In some embodiments, the termorgan used herein comprises a collection of different tissues joined instructure unit to serve a common function. In some embodiments, the termorgan used herein comprises a viscus, an internal organ, such as heart,liver, and intestine.

Noxipoint Therapy (NT) is useful and effective in reducing severechronic pain, restoring bodily function, and improving quality of lifewith substantial and sustained effects in patients with severe chronicneck or shoulder pain. NT is significantly more effective than theconventional PT, including TENS. A signaling pathway from C-fiberthrough phagocytosis to satellite cell regeneration shows the clinicalbenefits.

In some embodiments, the stimulation on the Noxipoints/Nocipointsincludes all forms of energy including IR (infrared), ultrasound, laserpulse, and any other forms of energy or stimulation.

In operation, the first and the second Noxipoints are identified and anamount of stimulations are applied on the Noxipoints with apredetermined chemical dosage or a predetermined electrical voltage witha preselected intensity, wave length, frequency, wave pattern or acombination thereof.

The present invention has been described in terms of specificembodiments incorporating details to facilitate the understanding ofprinciples of construction and operation of the invention. Suchreference herein to specific embodiments and details thereof is notintended to limit the scope of the claims appended hereto. It is readilyapparent to one skilled in the art that other various modifications canbe made in the embodiment chosen for illustration without departing fromthe spirit and scope of the invention as defined by the claims.

NT Versus Shame Therapy on Mechanical Hyperalgesia of the Rat

FIG. 12F illustrates the result of NK-like treatment to chronichypersensitivity in a rat study in accordance with some embodiments ofthe present invention.

Methods

Randomized controlled experiment of NT-like procedure versus shamcontrol is performed on adult male Sprague-Dawley rats, which arepurchased from BioLasco Company in Taiwan. Groups of 2 to 3 rats arehoused together in plastic cages and are placed in a temperature- andhumidity-controlled room (23±2° C. and 55±5%) with a 12-h light/darkcycle (lights on at 06:00 h). Food and water are available ad libitum.All animal care and experimental procedures are approved by theInstitutional Animal Care and Use Committee of National TaiwanUniversity (Approval No. NTU-103-EL-69). The study adhered to guidelinesestablished by the Codes for Experimental Use of Animals from theCouncil of Agriculture of Taiwan, based on the Animal Protection Law ofTaiwan.

The rats weighed between 260 and 400 g at the beginning of theexperiment. The repeated acid-injection-produced hyperalgesia model isused to induce chronic mechanical hyperalgesia following the Slukamodel. Acidic saline (pH 4.0) is prepared by adding HCl droplets tosterile saline. Two dosages of 100 μL of this acidic saline solution areinjected into the mid-belly of the left gastrocnemius muscle of the ratunder 4% isoflurane anesthesia. The two i.m. injections are separated byan interval of 5 days. Mechanical sensitivity is assayed by thethreshold force eliciting a lift of the hind limb by von Frey filament(North Coast Medical, Inc., Morgan Hill, USA) stimulation of the heelregion of the left hind paw. Each rat is individually placed on anelevated wire mesh floor in the transparent acrylic box (dimensions 21cm×12 cm×14 cm) and allowed to acclimate and withstood 15 g filamentstimulation before starting acid injections. On each test day, the ratis placed in the same chamber to acclimate 10 min. We applied the vonFrey filaments of various bending forces (0.6, 1, 2, 4, 6, 8, and 15 g).Brisk withdrawal or paw flinching is regarded as positive response.Threshold force is determined with the up-down procedure by Chaplan etal.

NT-like treatment starts on the third day after the second acidinjection. The same stimulator and the same stimulation parameters inthe patient treatment are used. The two poles of the stimulation areconnected to two separated pieces of aluminum foil of different widths.Under 4% isoflurane anesthesia, the wider foil is wrapped around theorigin of the gastrocnemius muscle, and the narrower one around the neckregion of the ankle (e.g., the insertion of the gastrocnemius muscle).Both pieces are half-circle shaped and care is taken to secure thecontact of the half circle to the gastrocnemius part of the leg. Theelectrical stimulation is applied for three minutes. The thresholdintensity that elicited ipsilateral lower leg contraction is defined as1T, and intensity (measured through an oscilloscope) of 2T is applied asNT-like treatment, based on the relative intensities of NT stimulationobserved in human patients, where to effective setting for NT is about1.5T to 2T (FIG. 12E). One of the two test groups is treated with NTonce on Day 0, and the other group treated by NT twice on Day 0 and Day3 respectively. The sham group underwent the same procedure ofanesthesia and electrode placement yet without stimulation. Mechanicalthreshold of the hind paws to von Frey stimulation is measured on 1, 4,7, 10, 14, and 21 days after the NT-like treatment. The window ofobservation of the induced hyperalgesia (Days 0-10) is dictated by thetime when the control group naturally exhibited reduced sensitivity(after Day 10). Two-Way Repeated Measures ANOVA (One Factor Repetition)followed by pairwise multiple comparison procedures (Tukey Test) is usedto analyze the data.

Results

NT-like therapy significantly reverses mechanical sensitization of thehind paw of rats (80.7% reduction in 2T-twice group at Day 3 andpersisted through Day 30; p<0.01) (See FIG. 12F), while the sham therapydoes not cause any change in the mechanical sensitization. It confirmedthe findings in human clinical trials.

In FIG. 12F, NT-like therapy reverses mechanical sensitization of thehind paw, which is produced by repeated injection of acid (pH=4)solution into the gastrocnemius muscle of the rat. On the third dayafter the second acid injection and a stable development of mechanicalsensitization (indicated by the drop of threshold force that producedhind paw withdrawal from 15 g to less than 4 g on Day 0), NT-liketreatment is given to the afflicted muscle at twice the thresholdintensity that caused gastrocnemius contraction (2T). Three groups ofrats (2T twice, 2T once, and sham control; 6 rats each) are tested. Thetreatment day is denoted as Day 0. Note that NP treatment for two times(2T twice, the red line) reversed mechanical sensitization of D1, D4, D7and D10. In the FIG. 12F, data using “*” refers to significantlydifferent NT outcome (p<0.01) in comparison with sham value on thematching days. Data using “+” refers to significantly different NToutcome (p<0.01) in comparison with 2T-once group. Data using “#” refersto significantly different NT outcome (p<0.01) in comparison withthreshold value before the acid injection (pre). Two-Way RepeatedMeasures ANOVA (One Factor Repetition) followed by pairwise multiplecomparison procedures (Tukey Test) are used.

In some embodiments, the testing results show that the optimal intensityfor most of both human and rats is between 1T and 2T, though >2T workedin some cases. In some embodiments, the presence ofvibration/contraction of a muscle (at intensity T) is used as apredicate to control the optimal setting of the NT stimulation (e.g.,slow down the increment of the intensity at T, and slow down furtherafter it reaches 1.5T or completely stop at 2T).

What is claimed is:
 1. A method comprising: a) identifying a pair ofNoxipoints, wherein the pair of Noxipoints are located at two terminalends of a muscle fiber; and b) applying a predetermined electrical orchemical stimulation to the pair of Noxipoints.
 2. The method of claim1, wherein the applying a predetermined electrical or chemicalstimulation to the pair of Noxipoints triggers a reaction of aneuroimmune cascade.
 3. The method of claim 1, wherein the chemicalstimulation comprises nociceptive chemicals.
 4. The method of claim 3,wherein the nociceptive chemicals comprises capsaicin.
 5. The method ofclaim 1, wherein the chemical stimulation comprises substance P,cytokines, growth factors, or a combination thereof.
 6. The method ofclaim 5, wherein the cytokines comprises TNF-α.
 7. The method of claim5, wherein the growth factors comprises IGF-1, HGF.
 8. The method ofclaim 5, wherein the chemical stimulation is delivered via injection orcutaneous patches to the target Noxipoints.
 9. The method of claim 1,wherein the electrical stimulation comprises increasing an appliedvoltage until an occurrence of a soreness, an achiness, a dull pain, ora combination thereof.
 10. The method of claim 1, further comprisingadjusting an intensity, a wave length, a train frequency, a wave patternof the applied electrical stimulation until the occurrence of thesoreness, the achiness, the dull pain, or the combination thereof. 11.The method of claim 1, wherein the pair of Noxipoints are located at twoattachments or ends of a muscle group or fiber.
 12. The method of claim1, wherein the pair of Noxipoints are located at two opposite sides ofan organ, distributed diffusely of the organ, or at the referral painpoints of the organ.
 13. The method of claim 12, wherein the referralpain points of the organ comprises brain cells.
 14. The method of claim1, wherein the applying a predetermined electrical or chemicalstimulation to the pair of Noxipoints enhances a growth rate of one ormore stem cells.
 15. The method of claim 1, wherein the applying apredetermined electrical or chemical stimulation to the pair ofNoxipoints activates one or more satellite cells or stem cells.
 16. Themethod of claim 1, wherein the applying a predetermined electrical orchemical stimulation to the pair of Noxipoints increases a rate ofself-healing process.
 17. The method of claim 1, further comprisingimmobilizing or constraining treated target cells, tissues, or organsfor a predetermined period.
 18. The method of claim 17, wherein thepredetermined period is estimated by a heuristic formula comprising age,physical conditions, or a combination thereof as parameters.
 19. Themethod of claim 18, wherein the physical conditions comprise weight,BMI, muscle conditions, or a combination thereof.
 20. The method ofclaim 17, wherein the immobilization or constraining comprises using oneor more assistive devices to constrain a use of the treated cell,tissue, or organ.
 21. The method of claim 17, wherein the one or moreassistive devices comprise cervical braces, shoulder support, wristbrace, back brace, canes, crutches, walkers, or wheel chairs.
 22. Atreatment device comprising: a) an user-interface control panelconfigured to have an option of control or to receive an input of aresponse of an applied electrical stimulation; and b) an electricalcontrol circuit configured to tune the applied electrical stimulation.23. The device of claim 22, wherein the option of control or theresponse comprises user's perceived sensation of soreness, achiness,dull pain, sharp pain or a combination thereof.
 24. The device of claim22, wherein the electrical control circuit or a software control isconfigured to continue increasing an applied voltage when aninput/response is not a sensation of a soreness, an achiness, a dullpain, a sharp pain or a combination thereof.
 25. The device of claim 22,further comprising a software system indicating a location of acorresponding Noxipoint of a pair of Noxipoints.
 26. The device of claim25, wherein the software system comprising a 3-dimensional modeling of ahuman anatomy and an indication of pairs of Noxipoints corresponding tothe injured organ.
 27. A method of enhancing a healing processcomprising: a) applying a predetermined stimulation on a pair ofNoxipoints; and b) enhancing a rate of healing by applying thepredetermined stimulation.
 28. The method of claim 27, wherein thepredetermined stimulation comprises an applied electrical stimulationuntil an occurrence of a soreness, an achiness, a dull pain, or acombination thereof.
 29. The method of claim 27, wherein thepredetermined stimulation triggers a signaling pathway of adifferentiation of one or more stem cells.
 30. The method of claim 27,wherein the predetermined stimulation triggers the generation or releaseof an amount of substance P.
 31. The method of claim 27, wherein thepredetermined stimulation makes an immune cell to release a histamineand a cytokine.
 32. The method of claim 31, wherein the immune cellcomprises a mast cell.
 33. The method of claim 31, wherein the cytokinecomprises tumor necrosis factor-alpha (TNF-alpha), hepatocyte growthfactor (HGF), or a combination thereof.
 34. The method of claim 27,wherein the predetermined stimulation causes a macrophage to conductphagocytosis on a scar tissue or an impaired tissue.
 35. The method ofclaim 27, wherein the predetermined stimulation comprises an externalapplication of an amount of substance P, TNF-α, growth factors, or acombination thereof.
 36. A method comprising: a) identifying a pair ofNoxipoints, wherein the pair of Noxipoints are located at thecorresponding nociceptors of an organ; and b) applying a predeterminedstimulation to the pair of Noxipoints.
 37. The method of claim 36,wherein the stimulation comprises electrical or chemical stimulation,infrared, ultrasound, laser, or a combination thereof.